Skeletal muscle atrophy diminishes the health and quality of life of tens of millions of people. Causes of muscle atrophy include aging, muscle disuse, malnutrition, critical illness, certain medications, and a wide range of chronic illnesses including cancer, heart failure, COPD, diabetes, renal failure, cirrhosis, rheumatoid arthritis, and HIV/AIDS. Effects of muscle atrophy include weakness, impaired activity, falls, prolonged hospitalization, delayed rehabilitation, loss of independent living, and increased mortality. Importantly, despite its prevalence and severity, skeletal muscle atrophy lacks a specific and effective pharmacologic therapy and thus represents an enormous unmet medical need. Development of pharmacologic interventions for muscle atrophy has been hindered by the fact that the molecular basis of muscle atrophy is highly complex, poorly understood, and still largely unexplored. The research proposed here would help to address this issue by investigating a stress-inducible molecular signaling pathway in skeletal muscle fibers that appears to be necessary and sufficient for muscle atrophy during at least 3 clinically important scenarios (aging, immobilization and fasting). We originally discovered this pathway through unbiased systems-based strategies, which have, to date, identified several critical pathway components, including Gadd45a (the pathway's centerpiece), ATF4 (an essential upstream regulator of the Gadd45a gene), and MEKK4 (an important downstream mediator of the Gadd45a protein). Our proposed studies will build upon these important initial findings to more deeply investigate and understand the upstream mechanisms that control Gadd45a expression (Aim 1), the pathophysiological consequences of Gadd45a expression in muscle (Aim 2), and the downstream mechanism(s) by which Gadd45a promotes muscle atrophy (Aim 3). These studies should significantly advance our understanding of how muscle atrophy occurs at the molecular level and facilitate achievement of several longer-term goals, the most important being the development of new therapeutic approaches for reducing muscle weakness and atrophy in people who are ill, injured and/or aged.